Crosstalk among Growth Factors, ADAMs and Integrins

生长因子、ADAM 和整合素之间的串扰

• 批准号: 6869734
• 负责人: MONIKA GOOZ
• 金额: $ 10.18万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869734
• 关键词: angiotensin receptor; cell surface receptors; enzyme activity; epidermal growth factor; growth factor receptors; integrins; kidney cell; laboratory rat; metalloendopeptidases; protein protein interaction; protein tyrosine kinase; receptor expression; serotonin receptor; tissue /cell culture

DESCRIPTION (provided by applicant): The goal of the present proposal is to study cross-talk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) that are present in physiological condition in renal mesangial cells. Specifically, we will study the involvement of metalloproteinases in this process. Further, we wish to study how extracellular matrix (ECM) receptors (called integrins) influence GPCR-RTK cross-talk in cultured mesangial cells. The specific aims of this proposal are: 1. To investigate whether activation of mitogenic Gq-coupled receptors (such as angiotensin II AT1A, serotonin 5-HT2A and LPA-Edg receptors) induce transactivation of the epidermal growth factor receptor (EGFR) by exogenous growth factor(s) through metalloproteinases in renal mesangial cells. a) If yes, we will examine whether these processes involve the same EGF-like growth factor (namely heparin-bound EGF) or whether distinct EGF-like growth factors are employed by the various GPCRs. b) We will also determine whether these shed ligands are processed by the same metalloproteinase(s), or by different ones depending on which GPCR is activated. Our initial focus will be on the TACE/ADAM 17 metalloproteinase. 2. To study the involvement of integrins and effects of changes in the ECM on GPCR-RTK cross-talk in mesangial cells. a) Is Gq-coupled receptor activation of ERK dependent on integrin-mediated cell anchorage? b) Which integrins are involved in GPCR-RTK cross-talk? c) Does overexpression of a TACE enzyme lacking the disintegrin domain alter signaling? d) Is physical interaction of TACE with integrins necessary for the GPCR-RTK cross-talk to occur?

描述(由申请人提供)： 本研究的目的是研究G蛋白偶联受体(GPCRs)和受体酪氨酸激酶(RTK)之间的相互作用，它们存在于肾小球系膜细胞的生理状态中。具体地说，我们将研究金属蛋白酶在这个过程中的参与。此外，我们希望研究细胞外基质(ECM)受体(称为整合素)如何影响培养的肾小球系膜细胞的GPCR-RTK串扰。 这项建议的具体目标是： 1.探讨促有丝分裂的GQ偶联受体(如血管紧张素II AT1A、5-羟色胺5-羟色胺2A和脂联素-EDG受体)的激活是否通过金属蛋白酶诱导外源性生长因子S反式激活肾小球系膜细胞的表皮生长因子受体。 A)如果是，我们将研究这些过程是否涉及相同的EGF样生长因子(即肝素结合的EGF)，或者不同的GPCR是否使用不同的EGF样生长因子。 B)我们还将确定这些脱落的配体是由相同的金属蛋白酶(S)还是由不同的金属蛋白酶处理的，这取决于GPCR被激活的情况。我们最初的关注点是TACE/ADAM 17金属蛋白酶。 2.研究整合素的参与及细胞外基质改变对系膜细胞GPCR-RTK串扰的影响。 A)GQ偶联的ERK受体激活依赖于整合素介导的细胞锚定吗？ B)哪些整合素参与了GPCR-RTK串扰？ C)缺乏去整合素结构域的TACE酶的过表达会改变信号吗？ D)TACE与整合素的物理相互作用是否需要GPCR-RTK串扰的发生？